1. Field of the Invention
The present invention is directed to methods and pharmaceutical compositions for treating the animal central nervous system for psychiatric disorders, including mood disorders, depression, schizophrenia and frontal temporal dementia.
2. Description of the Related Art
Certain medical procedures, for example coronary artery bypass graft (CABG) surgery, are associated with neurological complications. In the case of CABG, the surgery is performed on more than 800,000 patients worldwide each year. Many of the CABG procedures performed are associated with neurological complications. These complications range from stroke in up to 16% of the patients to general cognitive decline with 50% of patients having impairment post-surgery and with progressive decline occurring in some patients over the next five years. In addition, physical and behavioral impairment manifest in some CABG patients. Newman M F et al., N. Eng. J. Med. 344:395-402 (2001); Brillman J., Neurol. Clin. 11:475-495 (1993); and Seines, O. A., Ann. Thorac. Surg. 67:1669-1676 (1999) are instructive.
Originally, it was hypothesized that the neurological complications associated with CABG surgery were either procedure or patient-related. The procedure generally implicated as potentially harmful was cardiopulmonary bypass using a pump and oxygenator. However, a recent study reports no difference in cognitive outcome between groups of patients undergoing CABG surgery performed with, or without, the pump and oxygenator. Such results suggest that the neurological impairments following CABG surgery may, in fact, be patient-related and, as a result, amenable to therapeutic manipulation.
In addition, patients at risk for, or diagnosed with disorders involving neurological impairments, e.g., Alzheimer's disease, Parkinson's disease, stroke, traumatic brain injury, spinal cord injury may benefit from similar therapeutic manipulation. See Crapper McLachlan, D. R., Dalton, A. J., Kruck, T. P. A., Bell, M. Y., Smith, W. L., Kalow, W., and Andrews, D. F. Intramuscular desferrioxamine in patients with Alzheimer's disease. The Lancet 337:1304-1308, 1991. Further, mood disorders such as bipolar disorder and depression, ADHD, schizophrenia and frontal temporal dementia are conditions that are generally in the category of neurological impairment with symptoms that may be amendable to therapeutic intervention.
GSK-3β (GSK3b) is a serine/threonine kinase that has diverse functions in various cellular activities in many cell types, including glycogen synthesis, cell survival and cell division. Unlike most protein kinases, GSK3b is constitutively active and its activity is down-regulated by upstream signals through inhibitory phosphorylation. The most important and well-known target of GSK3b is the β-catenin transcriptional coactivator. Active GSK3b can directly phosphorylate β-catenin, resulting in ubiquitination-mediated proteasomal degradation of β-catenin. The NF-AT transcription factor has been found to be another target of GSK-3β, at least in T cells and neurons. Different from the β-catenin phosphorylation, NF-AT phosphorylation mediated by GSK3b promotes its export from the nucleus, therefore terminating NF-AT-dependent transcription. The NF-AT activation is counterbalanced by GSK3b and Ca2+-calcineurin. GSK3b phosphorylates NF-AT, leading to its nuclear export and transcriptional inactivation, while Ca2+-calcineurin dephosphorylates NF-AT, leading to its nuclear import and transcriptional activation.
Thus, GSK3b is a unique serine/threonine kinase that is inactivated by phosphorylation to form phosphorylated GSK3b (pGSK3b). In response to insulin binding, PKB/AKT phosphorylates GSK3b on serine 9, which prevents GSKb from phosphorylating glycogen synthase. Unphosphorylated glycogen synthase is active and able to synthesize glycogen. GSK3b is also unique in that it requires a substrate that has been phosphorylated by a distinct kinase before it can phosphorylate the substrate. The phosphate priming mechanism explains why phosphorylation of serine 9 inactivates GSK3b. The phosphorylated serine binds to the GSK3b priming phosphate position and prevents binding of alternative substrates. In addition to insulin signaling, GSK3b participates in the Wnt signaling pathway, where it forms a complex with axin, beta-catenin and adenomatous polyposis coli (APC) protein. In the presence of Wnt, GSK3b is unable to phosphorylate beta-catenin, which leads to stabilization of beta-catenin.
Moreover, the Akt/GSK3 signaling pathway plays a significant role in responses to dopamine, 5-HT and psychrotropic drugs, e.g., lithium, antidepressents and antipsychotics. Thus, this pathway and its diverse signaling molecules comprise important modulators of behavior. Regulation of this pathway by dopamine and 5-HT and three classes of psychotropic drugs (antipsychotics, mood stabilizers and antidepressants) indicates that Akt and GSK3 can act as signal integrators, allowing the precise coordination and cooperation of 5-HT and dopamine receptors signaling responses, with each other or with those related to other neutransmitters, hormones and/or growth factors. Thus, inhibition of GSK3b may provide a rationale for the effects of lithium, antidepressants and antipsychotics, which are often used in combination for various psychiatric conditions.
Studies suggest that inhibition of GSK3b may be a relevant target for the pathophysiology and treatment of psychiatric diseases including, e.g., bipolar disorder, also known as manic depression. A broader category of disease or condition may be termed mood disorders. Mood disorders include bipolar disorder, as well as patients experiencing major depression. Lithium is commonly used to treat mood disorders such as bipolar disorder and major depression and has been demonstrated to inhibit phosphorylation of GSK3b. In addition, valproic acid and electroconvulsive therapy also have been demonstrated to inhibit GSK3b. Studies convincingly demonstrate that GSK3b plays a critical role in depressive activity and the counteracting effects of antidepressents. Thus, the evidence indicates that inhibition of GSK3 contributes to the therapeutic action of these methods and agents. In addition, schizophrenia is associated with alterations in GSK3. See, e.g., Jope, “Glycogen Synthase Kinase-3 (GSK3) in Psychiatric Diseases and Therapeutic Interventions”, Curr Drug Targets, 2006 Nov.; 7(11): 1421-1434, the contents of which are incorporated in their entirety. GSK3b clearly plays a role in these psychiatric diseases and conditions and inhibition of GSK3b, i.e., by phosphorylation, is of therapeutic value.
Further, GSK3b inhibitors are of considerable interest because they mimic the effect of insulin and may reduce the hyperphosphorylation of Tau that is observed in Alzheimer's disease. Moreover, GSK3b inhibits the xenobiotic and antioxidant cell response by direct phsphorylation and nuclear exclusion of the transcription factor Nrf2, and GSK3b is involved in hydrogen peroxide-induced suppression of Tcf/Lef-dependent transcriptional activity.
Moreover, GSK3b plays a central role in impairment of cell neural plasticity and cell death or apoptosis. Neural plasticity includes the capacity of cells to respond to stress or harmful agents. Experimentally, this may be measured by assessing the terminal outcome of stress-induced death by apoptosis. Impairment of neural plasticity and apoptosis driven by GSK3b exposure are implicated in a wide variety of diseases and/or conditions: exposure to growth factor withdrawal and inhibition of the phosphoinositide 3-kiase/Akt signaling pathway, mitochondrial toxins, hypoxia/ischemia, glutamate excitotoxicity, endoplasmic reticulum stress, DNA damage, ceramide, oxidative stress, Alzheimer's disease-related amyloid b-peptide, prion peptide, polyglutamine toxicity, HIV-associated conditions, hypertonic stress to name a few. The skilled artisan will recognize the full depth and breadth of the relevant diseases and/or conditions. Control of GSK3b by phosphorylation will reduce impairment of cell neural plasticity as well as apoptosis that may lead, inter alia, to non-lethal but nevertheless critical and stressful conditions in psychiatric disorders such as bipolar disorder, depression, dementia and schizophrenia.
Certain agents or compounds may increase or promote phosphorylation of GSK3b. A particular example of such an agent is deferoxamine (DFO), a hexadentate iron chelator.
In vivo studies have demonstrated that DFO increases phosphorylation status of GSK3b in HepG2 cells of the rat liver supplemented with fetal calf serum wherein DFO-induced iron depletion improved hepatic insulin resistance. DFO has also been shown to promote phosphorylation status of GSK3b and increased b-catenin protein in bone morphogenetic protein-2 (BMP-2)-treated mesenchymal stem cells (MSC). Such findings demonstrate that, inter alia, DFO may likewise regulate osteoblast differentiation of MSC through the b-catenin pathway, which plays a critical role in BMP-2-induced osteogenic differentiation.
These studies involving inhibition by DFO of GSK3b through phosphorylation are in vitro studies involving the liver and bone. These studies do not make obvious the possibility that DFO could be used to, e.g., treat psychiatric disorders within the brain and central nervous system for a variety of reasons.
For example, problems exist with the administration of DFO intravenously. DFO is not generally injected intravenously for at least three reasons. First, it is a small molecule and, as a result, is eliminated rapidly through the kidney. The typical plasma half-life in humans is less than 10 minutes. Second, the injection of an intravenous bolus of DFO causes acute hypotension that is rapid, may lead to shock and may be lethal. Third, intravenously or systemically administered DFO does not efficiently or effectively cross the blood-brain barrier. These characteristics have limited the utility of DFO in particular as a neuroprotective agent.
One published study administered DFO generally intranasally to iron overloaded patients. G. S. Gordon et al., Intranasal Administration of Deferoxamine to Iron Overloaded Patients, (1989) Am. J. Med. Sci. 297(5):280-284. In this particular study, DFO was administered to the patients as a nasal spray in a volume of 75 microliters per spray. Significantly, such sprays are known to deposit the drug or other substance in the lower third of the nasal cavity. This is verified by patient observations stating that a bad taste in the mouth was resulting from the drug passing through the nasopharynx and into the mouth. As a result, this study did not involve delivering the drug to the upper third of the nasal cavity. Thus, the drug would not have reached the olfactory epithelium or the olfactory nerves. As a result, delivery of the drug to the CNS would be less than optimal.
It is recognized that agent delivery to the CNS may occur along both the olfactory and trigeminal nerve pathways. See Thorne, RG (2004), Delivery of Insulin-Like Growth Factor-I to the Rat Brain and Spinal Cord Along Olfactory and Trigeminal Pathways Following Intranasal Administration, Neuroscience, Vol. 127, pp. 481-496. Optimal delivery taking advantage of both pathways is accomplished by administering the substance in the upper third of the nasal cavity.
It would be highly desirable to directly deliver an effective amount or dose of DFO to the upper one-third of the patient's nasal cavity, thereby bypassing the blood-brain barrier for treatment of diseases or conditions which are affected by non-phosphorylated GSK3b. As discussed, DFO stimulates phosphorylation of GSK3b, thereby inactivating or inhibiting GSK3b and thus therapeutic for patients suffering from certain psychiatric mood disorders (bipolar disorder and depression) as well as patients with schizophrenia and frontal temporal dementia. Therapy provided by the present invention, i.e., inactivation of GSK3b by DFO-stimulated phosphorylation of GSK3b may also be used to treat patients suffering from memory loss in a variety of conditions, including but not limited to Alzheimer's disease.